Methotrexate (MTX), a drug used in cancer chemotherapy and in the treatment of psoriasis, is known to impair DNA and RNA synthesis by antagonizing folate metabolism. A major side-effect of this drug is the formation of a fatty liver and eventual cirrhosis of the liver. Since levels of certain lipotropic substances in the liver are also synthesized de novo by way of folate-dependent 1-carbon metabolism, this study was conducted to determine if the side-effects of MTX may be a consequence of interference with 1-carbon metabolism in the liver. This study investigated the effect of MTX on hepatic and serum lipid content when various lipotropes were administered to rats fed a diet deficient in methionine, choline and vitamin B12. Results demonstrate that MTX can potentiate a choline-deficient fatty liver and block the lipotropic effect of vitamin B12. They also show that methionine and choline, products of 1-carbon metabolism beyond folate involvement, overcame the detrimental effects of MTX. This suggests that MTX interferes with hepatic methyl group genesis and hence blocks the de novo synthesis of methionine and choline. BIBLIOGRAPHIC REFERENCES: Tuma, D.J., Barak, A.J., Sorrell, M.F. Interaction of methotrexate with lipotropic factors in rat liver. Biochem. Pharmacol. 24:1327 (1975).